A Review of Melioidosis Cases Imported Into Europe

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European Journal of Clinical Microbiology & Infectious Diseases (2019) 38:1395–1408 https://doi.org/10.1007/s10096-019-03548-5

REVIEW

A review of melioidosis cases imported into Europe

Sarah Le Tohic1 & Marc Montana2,3 & Lionel Koch4 & Christophe Curti2,5 & Patrice Vanelle 2,5

Received: 8 February 2019 /Accepted: 25 March 2019 /Published online: 4 April 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract Melioidosis is a tropical bacterial infection, rarely encountered, and poorly known by clinicians. In non-endemic areas, a misdiagnosis can lead to a fatal outcome. This study aims to identify the main characteristics of imported and diagnosed melioidosis cases in Europe to increase clinician’s awareness of this diagnosis. A literature review of imported and diagnosed human melioidosis cases in Europe was performed. PubMed and Web of Science search engines were used for retrieving articles from 2000 to November 2018. Seventy-seven cases of imported melioidosis into Europe described in the literature were identified. More than half of the cases were acquired in Thailand (53%) by men (73%). Patients were usually exposed to Burkholderia pseudomallei during a holiday stay (58%) of less than 1 month (23%) and were hospitalized during the month following their return to Europe (58%). Among travelers, melioidosis is less often associated with risk factor (16%), diabetes being the most frequently comorbidity related (19%). The clinical presentation was multifaceted, pneumonia being the most common symptom (52%), followed by cardiovascular form (45%) and skin and soft tissues damages (35%). The diagnosis was obtained by culture (92%), often supplemented by morphological, biochemical, and molecular identification (23%). Misdiagnoses were common (21%). Over half of the patients received a complete and adapted treatment (56%). Mortality is lower for returning traveler (6%). Imported melioidosis cases into Europe have their own characteristics. This possibility should be considered in patients with pneumonia, fever, and/or abscess returning from endemic areas even years after.

Keywords Melioidosis . Pneumonia . Travel medicine . Case reports

Introduction

Melioidosis is a tropical bacterial infection, caused by a bacil- Electronic supplementary material The online version of this article lus Burkholderia pseudomallei, formerly known as (https://doi.org/10.1007/s10096-019-03548-5) contains supplementary Pseudomonas pseudomallei, Malleomyces pseudomallei,or material, which is available to authorized users. Bacillus whitmori. Each year, there are nearly 165,000 cases worldwide and 54% are estimated to be fatal [1]. The mortal- * Sarah Le Tohic ity burden is similar to that of measles [2]. Melioidosis is [email protected] endemic in Southeast Asia, Northern Australia, India, and China. This disease sporadically occurs in tropical areas be- 1 ’ Hôpital d Instruction des Armées Laveran, Marseille, France tween the 20th of northern and southern parallels [3]. 2 Laboratoire de Pharmaco-Chimie Radicalaire, Aix Marseille Univ, Melioidosis is extremely rare in the temperate zone: they are CNRS, ICR, Marseille, France, Marseille, France essentially imported cases by travelers or immigrants [4]. But 3 Assistance Publique-Hôpitaux de Marseille (AP-HM), Oncopharma, global warming and mass international travel in Asia can in- Hôpital Nord, Marseille, France crease the incidence in non-endemic areas [2]. 4 Institut de Recherche Biomédicale des Armées (IRBA), Pseudomonas pseudomallei is an environmental Gram- Brétigny-sur-Orge, France negative bacterium found in soil and surface water, especially 5 Service central de la qualité et de l’information pharmaceutiques during the rainy season. Community-acquired infections in (SCQIP), Assistance Publique-Hôpitaux de Marseille (AP-HM), human results from exposure through wounded skin, inhala- Marseille, France tion, or ingestion. Nosocomial infections have been rarely 1396 Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408 reported [5]. Melioidosis is not considered to be a contagious of Science (Thomson Reuters Scientific—https://www. infection and human-to-human transmission is very rare [3, 5]. webofknowledge.com/) to identify all published case reports This emerging disease is pleomorphic and opportunistic of melioidosis imported in humans into Europe. The literature because it can affect various organs and displays different search included English-, German-, and French-language ar- clinical presentations from chronic disease to sepsis and death. ticles and publications in other languages if informative ab- Nevertheless, the leading form of melioidosis is pulmonary stracts in the English language were available. disease, as this pathogenic agent is unknown in non-endemic Search terms were selected to detect case reports published areas and it can be easily mistaken for other diseases, such as about imported melioidosis applying exclusion criteria. The community-acquired pneumonia or tuberculosis. So, it is often following terms combinations were applied: Bmelioidosis^ referred to as Bthe Great Mimicker^ [4]andremains OR BBurkholderia pseudomallei^ OR BPseudomonas underdiagnosed. The first diagnosis is based on biochemical pseudomallei^ OR BMalleomyces pseudomallei^ OR tests and morphology identification of bacterium. Molecular BWithmore bacillus^ in human. The Boolean operators were biology is also essential to limit the risk of confusion but takes varied according to the rules of each specific database. longer to obtain. However, early diagnosis and treatment are Searches were conducted using the final limit dates of crucial to reduce mortality, which may reach up to 87% with- January 1, 2000 and November 15, 2018. out treatment [6]. Currently, no vaccine is available and Pseudomonas pseudomallei is widely resistant to several an- Study selection tibiotics, such as gentamicin, colistin, and rifampicin. The bacterium is most often susceptible to ceftazidime, The review was performed in two main stages, as described by meropenem, and amoxicillin–clavulanate. Matos [11]. Eligibility criteria were predetermined by the au- In most European countries, melioidosis is not a nationally thors (Table 1). In the first step, they independently reviewed notifiable disease, making it difficult to ensure epidemiologi- the titles and abstracts yielded by this comprehensive search cal surveillance. However, Pseudomonas pseudomallei is a and subsequently selected articles based on the predetermined selected agent according to the US federal law and belongs inclusion criteria. Any reservations on eligibility for inclusion to Tier 1 agent list of the Centers for Diseases Control and were resolved by discussion between reviewers. After remov- Prevention (CDC). In France, the possession of this organism al of duplicates, the authors read each selected full text and is subject to the regulation on highly pathogenic microorgan- eliminated articles fitting the exclusion criteria. During this isms and toxins (MOT) and must be handled in a biosafety second stage, the references of relevant articles were exam- level 3 laboratory. All these rules and regulations are ex- ined to identify additional cases not found in computerized plained by the high pathogenicity of the bacteria and by its databases. possible use as bioterrorism agent [7–9]. Melioidosis has the potential to become a real public health Data extraction process problem, considering its rising incidence, misdiagnosis, therapeutic difficulties, high mortality, and induced biological risk The data collected from all included studies are as follows: [2, 7, 10]. So, we decided to conduct a systematic review of year and country of diagnosis or publication, basic demo- melioidosis cases imported and diagnosed in human in Europe graphic characteristics (age, gender, ethnicity, and socio- since 2000 to increase clinicians’ awareness of its diagnosis. professional category), underlying diseases, foreign travel history (type, country, and duration (< 1 month, 1–6months,> 6months[4], or unknown)), route of exposure, manifestations Materials and methods and care in endemic area, time between arrival in Europe and hospitalization (< 1 month, 1–6 months, > 6 months [4], or Background definitions unknown), clinical manifestations (included fever, pulmonary symptoms, weightless [12],, abscess and localization, bacter- The search method employed in this systematic review was to emia), source of the B. pseudomallei isolates, method used identify and select case reports of imported melioidosis in (phenotype, molecular biology, spectrometry), complementa- humans in Europe. Information on clinical characteristics, ex- ry examinations, researched pathogen agents and misdiagno- posure history, comorbidities, management, and outcome sis, treatments and duration, observed adverse effects, resis- were abstracted. tance to recommended antibiotics, length of follow-up, and outcome (cure, recurrence, death, and unknown). Data sources and searches Morphological and biochemical identification (VITEK 1 and 2, API 20 NE (bioMérieux, Marcy l’Etoile, France)) are We searched MEDLINE/PubMed (National Library of grouped under the name of the phenotype. Molecular biology Medicine—https://www.ncbi.nlm.nih.gov/pubmed)andWeb includes sequencing of 16SrRNA, PCR (polymerase chain Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408 1397

Table 1 Inclusion and exclusion criteria

Parameter Inclusion Exclusion

1 Language German, English, French, other languages if Any other language without informative informative abstracts in English language abstract in English were available 2 Type of study Clinical characteristics, exposure history, Exclusively in vitro articles that focus only on comorbid conditions, management, biological parameters and outcome 3 Type of publication Original manuscript, conference abstracts, Reviews, book chapters, table of contents, thesis personal opinions, indexes, letters 4 Search terms - Merely citing keywords in text 5 Localization Diagnosed and imported melioidosis in Europe Diagnosed cases of all other geographic regions Nosocomial infections reaction), and real-time PCR. Spectrometry names mass spec- Europe. A final total of 67 records were included in this re- trometry, with or not MALDI-TOF (matrix-assisted laser de- view, describing 77 different cases of melioidosis [17–83]. sorption ionization—time of flight). Recurrence was defined This process is illustrated by a flow diagram in Fig. 1. as a clinical feature of melioidosis in association with one or more cultures positive for B. pseudomallei in a patient with a history of one or more previous episodes. Epidemiology Treatment consists of an initial intensive phase by intravenous followed by the oral maintenance eradication phase to The majority of cases were described in 2005 after the 2004 prevent relapse (Table 2). We have referred to current recom- Indian Ocean tsunami [57, 59, 60, 64] and in 2010, with the mended practices at the time of publication. Before 2014, we release of a set of five cases in Denmark [48](Fig.2). took the recommendation of the French Agency for the The demographic and epidemiologic characteristics of the Medical Safety of Health Products [13] and international lit- 77 cases are presented in Table 3. The mean age was 46 ± erature as guidelines [12, 14–16]. Eradication phase recom- 17 years, with a median of 47 [11–90] years. The sex ratio of mendations vary from country to country, except for trimeth- male/female was 2.7. Ethnicity was identified in only 30% of oprim–sulfamethoxazole, always prescribed. Since 2014, in- cases, with a majority of Caucasian and Asian origins. Socio- ternational recommendations have changed [4, 6, 14, 84, 85]. professional category was specified in only 4 cases (frame Duration depends on the clinical condition of the patient and worker [32], psychiatry instructor [47], basketball trainer monotherapy of trimethoprim–sulfamethoxazole without in- [54], student [25]). tensive phase may be enough in some localized and minor Travelers were coming back from four different continents: cutaneous infections. Doses are not being taken into account 86% from Asia (66 cases), 9% from Africa (7 cases), 5% from despite their importance because the majority of publications America (4 cases), and 3% from Oceania (2 cases). Three did not report them. patients traveled through several continents (Southeast Asia All graphics and figures have been generated with Excel and Africa or America or Oceania). Thailand was by far the and Powerpoint (Microsoft). A library of all relevant refer- leading single country where travelers acquired the infection, ences was built using Zotero software (www.zotero.org)for with 41 cases (53%), followed by Vietnam and Cambodia, bibliographic management. each with 7 cases (9%). Melioidosis was essentially reported in Western Europe in 68% of cases. This infection was most often acquired during holidays of less than 1 month abroad and probably caused by percutaneous inoculation. Patients Results were taken care of within 1 month after returns to Europe. The development of melioidosis could be facilitated by risk The database search identified 633 records. After the first factors (exposure and comorbidity), described in Table 4. evaluation phase (title/abstract), 577 records were excluded. Twenty-seven patients were exposed to several exposure risk Fourteen repeated files were discarded, leading to 56 citations. factors (from two to six). The most common was skin injury To the remaining articles, 14 publications were added from the and/or insect bites, which led to suspect contamination by reference lists of the identified studies (which had not been percutaneous inoculation. Fifteen patients had multiple co- found in the initial search). Phase 2 was therefore conducted morbidities (from two to four), especially an age over 45 years, with a total of 70 articles. After the full-text reading, three diabetes and chronic lung diseases or smoking tobacco or articles were excluded because of their localization outside cannabis. 1398 Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408

Travelers who died from melioidosis were only men returning from holidays abroad, mainly from Southeast Asia (80% of cases) and were hospitalized within 1 month after. In 60% of cases, they were diabetics and over age 45. During clavulanic sulfamethoxazole –

– their holidays, 80% of them were exposed to at least one risk factor, varying from one patient to another.

Clinical presentations , or intensive care transfers The clinical characteristics of the imported cases are detailed in Table 5. Most travelers were symptom-free during their trip

acid or doxycycline and only 11 patients received an empiric antibiotic therapy in Eradication (PO) First-line therapy: trimethoprim Second-line therapy: amoxicillin At least 3 months Severe infection****: 6 months an endemic area. The most common clinical presentation was pneumonia followed by cardiovascular involvement, cutaneous and soft tissue infections. Several presentations were associated in 44 bscess, persistent bacteremia patients. More than half of the patients presented fever, pul- 17 ]

sulfamethoxazole monary symptoms, and/or abscess. They were localized on – 14 ,

, the skin, soft tissue, and lungs. Several sites were identified 4 in 14 patients (Supplementary Table 1). Four mycotic aneu- 83 ] rysms have been described. Bacteremia occurred in nearly 8 months 69 – – 14 days Severe infections***: Severe infections**: trimethoprim 4 half of patients. 17 , Intensive (IV) Ceftazidime or meropenem Since 2014 [ 10 – [ Three of five patients who died developed symptoms dur-

,peros ing their trip and two of them received an empiric antibiotic

PO therapy. Four patients had a fever. Bacteremia and pneumonia occurred in all of them, four with an abscess and one with a gastrointestinal presentation. , intravenous and clavulanic acid sulfamethoxazole

IV Diagnosis –

Melioidosis diagnostic is most often based on blood samples and abscess material cultured. Blood cultures trimethoprim (ever), doxycycline, chloramphenicol, or– amoxicillin were informative in 38 patients (49%) (Table 6; Eradication (PO) Simple, double, or triple therapy: soft tissue infections, or genitourin ary infection, including prostatic a

tatic abscess, neurological melioidosis, or septic arthritis Supplementary Table 2). Bacillus was mostly identified thanks to its morphological, biochemical, and molecular 12 ] characteristics. Medical imaging completed 79% of these results and biopsy, 26% (Supplementary tazobactam – Table 3). CT scan was informative in 33 cases (43%), radiography in 25 cases (32%), and ultrasound in 13 16 ]) 24 weeks cases (17%). Another germ was suspected and investi- –

14 , gated among 35% of travelers (27 cases), primarily py: piperacillin 12 ,

3to12 Mycobacterium tuberculosis (14 cases). Wrong bacteria 16 ] – sulfamethoxazole

– have been identified in ten travelers, including 12 – B. cepacia (4 cases) and B. thailandensis (4 cases) with biochemical and spectrometric methods. Nineteen misdi- 20 weeks* (eradication phase) 68 ]

– agnoses were made (25%), generally pneumonia or uri- (France, [ 13 ]) 8 (endemic areas, [ Severe infections: adding doxycycline or trimethoprim Second-line thera 18 – 10 days (intensive phase), followed by Before 2014 [ nary infection. Travelers who died from melioidosis were diagnosed using Treatment recommendations of melioidosis before and since 2014, with blood culture, morphologic and biochemical test identification, and/or molecular biology. Salmonella was suspected Table 2 Phases Intensive (IV) Antibiotics First-line therapy: carbapenem or ceftazidime Patients [ Duration 20 weeks from 2 *Neurological melioidosis, osteomyelitis, septic arthritis, skin and *At least 12 weeks, except for acute suppurative parotitis [ **Complicated pneumonia, deep-seated infection, including pros ***Neurological infection or osteomyelitis and investigated in two of these patients (Table 6). Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408 1399

Fig 1 Flow diagram of study selection adapted from Matos [11]

Treatment treatment and one (1%), a vascular filling. Nine patients (12%) were not treated. Before the identification of Pseudomonas pseudomallei,48 Forty-three patients (56%) received a comprehensive and patients (62%) were treated with an empiric antibiotic therapy consistent with guidelines treatment (Table 2). Intensive anti- including all patients who died. Twenty-four surgical drain- biotic treatment and duration were appropriate to 79% and ages were carried out (31%). Three (4%) have received a local 82% of travelers, respectively (Table 7). Thirty-six patients 1400 Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408

14 Table 3 Epidemiologic characteristics of 77 cases of melioidosis in 12 travelers reported in the literature

10 Cases Deceased 8 N (% of total) N (% per category) Total 77 5 6

Occurrences 4 Age – 2 <18years 3(4) 18–45 years 34 (44) 2 (6) 0 46–74 years 38 (49) 3 (8) ≥ 75 years 2 (3) – Year of publication Gender Fig. 2 Number of melioidosis cases imported into Europe, per Male 56 (73) 5 (9) publication year, from 2000 to 2018 Female 21 (27) – received ceftazidime (47%), 23 meropenem (30%), and 3 Ethnicity – piperacillin–tazobactam (4%) (Supplementary Table 4d). Africa 1 (1) – Treatment was given from 1 day to 5 months; the duration Afro-Caribbean 1 (1) – was too short in only 3 cases. Caribbean 1 (1) – Regarding maintenance treatment, more than 70% of trav- Caucasian 10 (13) – elers were treated by an appropriate antibiotic for a sufficiently Southeast Asia 7 (9) – long period. Trimethoprim–sulfamethoxazole was used in 50 Sub-Saharan Africa 3 (4) patients (65%), as monotherapy in 40% of them. Doxycycline Unknown 54 (71) 5 (9) was administered in 34 patients (44%), as monotherapy in 3 Type of trip patients. Fourteen patients (18%) received amoxicillin– Business 4 (5) – clavulanic acid, as monotherapy in 3 patients too. Adverse Family and relatives 10 (13) – effects on 10 of the 71 treated patients (14%) were reported, Indigenous 2 (3) – including trimethoprim–sulfamethoxazole (7 cases), ceftazi- Tourism 45 (58) 5 (11) dime (2 cases), amoxicillin–clavulanic acid (1 case), and Unknown 16 (21) – doxycycline (1 case). Only 14 antibiotic resistances were doc- Country of diagnosis umented in 13 patients [22, 24, 32, 47, 48, 63, 66, 70, 72, 76, Austria 2 (3) 1 (50) 79, 83], involving trimethoprim–sulfamethoxazole (8 cases, Belgium 3 (4) – 10%), amoxicillin–clavulanic acid (4 cases, 5%), doxycycline Denmark 9 (11) 1 (11) (1 case, 1%), and meropenem (1 case, 1%). Finland 4 (5) – Thirty patients were followed up post-treatment during on France 17 (22) – average 1 year and 4 ± 10 months, from 0 to 3 years. Sixty- Germany 13 (17) – five travelers were cured (84%). Among these, three had Holland 4 (5) 1 (25) shown sequelae and one after first relapse. Three patients Italia 4 (5) – (4%) relapsed including one with antibiotic resistant and five Norway 3 (4) – have died (6%). No information was available for five trav- Portugal 1 (1) – elers (6%). Slovenia 1 (1) – Most deceased patients received adequate acute treatment. Spain 2 (3) – But the death occurred quickly and only one patient was treat- Sweden 2 (3) – ed by maintenance treatment. (Supplementary Table 4). Switzerland 3 (4) 1 (33) United Kingdom 9 (12) 1 (11) Exposure area(s)* Discussion Africa 7 (9) – Caribbean 3 (4) 1 (33) Epidemiology China 1 (1) – India 1 (1) – All patients included in the study traveled in an endemic area, Oceania 2 (3) mainly in Southeast Asia [1, 4]. Thailand is the leading risk South America 1 (1) 1 (100) country. Indeed, it represents a very popular touristic destina- Southeast Asia 65 (84) 4 (5) tion with 35.4 million travelers in 2017. Only three cases were Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408 1401

Table 3 (continued) comorbidity (Table 8) with no clear explanation. Part of this Cases Deceased difference could be explained by the organization and efficien- N (% of total) N (% per category) cy of the health care system that previously recorded it. In Total 77 5 most country, where Pseudomonas pseudomallei is endemic, underreporting is highly plausible and unavailability of capac- – Unknown 1 (1) itated laboratories for diagnosis is conceivable. We might as- Exposure duration sume that naive people, such as travelers, may be more vul- <1 month 18(23) 3(17) nerable than indigenous people, even to have genetic factors – 1to6months 9(12) limited disease as the result of selection pressure [90]. – > 6 months 12 (16) Consistent with the literature, the major comorbidity exclud- Unknown 38 (49) 2 (5) ing age remains diabetes [85]. Chronic lung disease and Route of exposure smoking are more common in our study than it is usually Percutaneous inoculation 28 (36) 3 (11) described [22, 88]. Other comorbidities rank in the same order Percutaneous 6(8) 1(17) as in the previous studies [22, 88, 89]. Thalassemia is often inoculation/ingestion Inhalation 6 (8) – mentioned as a risk factor [4], but a single case of melioidosis infection in such a patient was reported in Europe since 2000. Ingestion –– Indeed, this blood disorder is most common in tropical and Unknown 37 (48) 1 (3) subtropical areas where the melioidosis is endemic. In Europe, Time between arrival in Europe and hospitalization the Mediterranean Basin is the only region that still reports <1 month 37(48) 5(14) thalassemia cases [91, 92]. 1–6months 17(22) – > 6 months 11 (14) – Clinical presentations Unknown 12 (16) –

*Some patients traveled to several risk areas The absence of symptoms in the endemic area could be explained by an incubation period to 21 days, with a median of 9days[4], and by the high frequency of short stays. reported in central and eastern Europe. This discrepancy with Among travelers, the pulmonary presentation is most often western and northern Europe could be explained by a higher occurred, followed by cardiovascular damages and skin and proportion of low-income households, international tourism soft tissue infections, on the same level as indigenous cases less often and more difficult access to molecular biology. [4]. Only the results of Dan et al. are halved from similar There is no indigenous case in Europe but the situation might studies, which could be explained by a lack of initial data change in the years to come due to global warming and the (Table 8)[88]. Bacteremia has been reported in 43% of cases, increase in people mobility, like in the USA [86, 87]. which is in accordance with worldwide data (Table 8)[4]. The In our study, melioidosis was usually diagnosed shortly spectrum of clinical signs is due to opportunistic and adapt- after returning to Europe, which also corresponds to our re- able Pseudomonas pseudomallei characteristics. The clinical view of the scientific literature which describes an incubation presentation depends on the mode of contamination and the period of 1 to 21 days [3, 4, 88]. However, latent infections are infected tissue [4]. In contrast to that described in indigenous possible several years after exposure [4]. The shorter the in- people, weightless is not related to highest mortality among cubation period is, the more severe the infection could be [4]: European travelers. Only one of the five deceased patients has the five deceased patients in our study were all hospitalized lost weight [4]. within 1 month after returning to Europe. For three of them, Melioidosis clinical picture is not specific. This diagnosis symptoms appeared during their trip. Our data are similar to should be considered for a patient with pneumonia, fever, or those found in the literature of imported cases: melioidosis is abscess returning form endemic area, even several years after. most common in man in his fifties (Table 8). Indeed, being In this case, it is important to encourage patient to remember aged more than 45 years old is a risk factor known for this his trip and potential risk situations, if melioidosis diagnosis is infection [4]. However, the average age tends to decline prob- not excluded. ably because travel is becoming more and more popular among young people for holidays and work. Diagnosis Exposure factors correspond to those found in the literature, including skin lesion, rainy seasons, natural disasters, Melioidosis is a diagnostic challenge. Biological signs are not and traveling in the rural and dusty area [4]. relevant. Medical imaging helps only to localize the infected In contrast to indigenous melioidosis and imported cases in site. Detection rate is low and European practitioners have a Japan [4, 89], only 44% of travelers had at least one lack of experience [93]. The non-specificity of symptoms 1402 Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408

Table 4 Risk factors of 77 cases of melioidosis in travelers Risk factors Patients Deceased reported in the literature N (% of total) N (% per category)

Exposure Skin lesion, insect bites 23 (30) 2 (9) Natural disaster (flood, hurricane, tsunami, etc.) 12 (16) 1 (8) Rural and/or dusty areas 12 (16) 3 (25) Rainy season 9 (12) – Moist soils (rice fields, river, muddy soils, etc.) 6 (8) 1 (17) Resident, frequent trips 6 (8) – Surface/non-potable/stagnant water, nautical sport, freshwater bathing 6 (8) 3 (50) Walking barefoot 2 (3) – Comorbidity* Diabetes 15 (19) 3 (20) Chronic lung diseases, smoking, cannabis (with 1 detoxed) 15 (19) – Cirrhosis, hepatic disease, alcoholism (with 2 detoxed) 11 (14) – Immunosuppression 6 (8) – Chronic kidney disease 4 (5) 1 (25) Cancer 3 (4) – Thalassemia 1 (1) – Recent fracture 1 (1) – Patients aged 45 or older 41 (53) 3 (7) With at least one risk factor With at least one exposure factor 46 (60) 4 (9) With at least one comorbidity increased melioidosis development 34 (44) 3 (9) No risk factor Exposure factor 1 (1) – Comorbidity increased melioidosis development 32 (42) 2 (6) Unknown Exposure factor 30 (39) 1 (3) Comorbidity increased melioidosis development 11 (14) –

Some patients have been exposed to several exposure factors and/or several comorbidities *Other comorbidities: atrial fibrillation, stable angina, arterial hypertension, peripheral arterial disease, dyslipid- emia, obesity, diverticulitis, gastritis, appendectomy, asymptomatic lithiasis, acanthosis nigricans, dengue, hypo- thyroid, treated Graves’ disease, ophthalmic tuberculosis, benign prostatic hyperplasia enhances misdiagnosis in travelers and in indigenous patients. is problematic both for the patient because it delays its M. tuberculosis is the leading pathogen sought, because of treatment but also for those around him due to the risk of pulmonary symptoms, which usually occurred and are very nosocomial infections in certain circumstances [4, 5, 86]. suggestive of tuberculosis disease. Melioidosis is often re- Several techniques must be used to exclude melioidosis. ferred to as Bthe Great Mimicker^ [4, 93]. In our study, other Bacteremia is usually observed, and this is why blood pathogens have been sought for 26 patients (34%) because cultures are the most informative samples. They are pos- practitioners may have had no idea of diagnosis. itive in 50 to 75% of patients in the literature [4, 94]and The culture of the bacterium is the mainly diagnostic in near 50% in our study. Repeated samples and selective method in our study (92%), as suggested in recommen- media may be used when there is a melioidosis suspi- dations [4]. As this pathogen must be handled in biosafe- cion. Due to the low growth of Pseudomonas ty level 3, this raises biosafety issues in laboratories pseudomallei anincubationtime,upto6daysmaybe where routine analyses are performed in biosafety level required. In order to limit the infection consequences, 2. Furthermore, Pseudomonas pseudomallei could be germ can be rapidly detected by immunofluorescence, easily identified as a contaminant or confused with other as this technic is very specific but not very sensitive bacteria, even with biochemical and spectrometric [4]. However, this method was not used in our study. methods [4], which can lead to delayed diagnosis. This Among the diagnostic, arsenal molecular biology is the Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408 1403

Table 5 Clinical presentations of 77 cases of melioidosis in travelers reported in the literature

Total Bacteremiastatus

Bacteremia No bacteremia

Patients Deceased Patients Deceased Patients Deceased N (% of total) N (% per category) N (% per category) N (% per category) N (% per category) N (% per category)

In endemic area Symptomatic 24 (31) 3 (13) 12 (50) 3 (100) 12 (50) – Treatment* Antibiotics 11 (14) 2 (18) 6 (55) 2 (100) 5 (45) – Local 7 (9) – 2 (29) – 5 (71) – Symptomatic 3 (4) – 3 (100) ––– None 12 (16) 1 (8) 2 (17) 1 (100) 10 (83) – Unknown 48 (62) 2 (4) 22 (46) 2 (100) 26 (54) – In Europe Clinical presentations** [4] Cardiovascular 35 (45) 3 (9) 32 (91) 3 (100) 3 (9) – Cutaneous, soft tissue 27 (35) – 8 (30) – 19 (70) – Gastrointestinal 13 (8) 1 (8) 8 (62) 1 (100) 5 (38) – Neurological 5 (6) – 2 (40) – 3 (60) – Osteoarticular 14 (18) – 4 (29) – 10 (71) – Pulmonary 40 (52) 5 (13) 21 (53) 5 (100) 19 (47) – Genitourinary 7 (9) – 5 (71) – 2 (29) – Many 44 (57) 3 (7) 30 (68) 3 (100) 14 (32) – Symptoms Fever 52 (68) 4 (8) 30 (58) 4 (100) 22 (42) – Weight loss 9 (13) 1 (11) 4 (44) 1 (100) 5 (56) – Pulmonary symptoms 39 (51) 5 (13) 25 (64) 5 (100) 14 (36) – Lesion 14 (18) – 3 (21) – 11 (79) – Abscess 46 (60) 4 (9) 20 (43) 4 (100) 26 (61) – Total 77 5 33 (43) 5 (100) 44 (57) –

*Some patients have received several treatments in endemic areas **Some patients have had different clinical presentations Cardiovascular: aneurism mycotic, pericarditis, bacteremia Cutaneous, soft tissue: cutaneous ulcer, cutaneous abscess, soft tissue abscess, neck abscess, lymphadenitis Gastrointestinal: hepatic abscess, splenic abscess, para-intestinal mass Neurological: cerebral abscess Osteoarticular: osteomyelitis, myalgia, muscular abscess, bone damage, pyomyositis, bursitis Pulmonary: pneumonia, pulmonary abscess, pleural abscess Genitourinary: acute pyelonephritis, kidney abscess, prostatic abscess most precise but is limited to research and reference cen- In our study, antibodies were identified in 9% of travelers. ters. There are several instances [27, 30, 37, 38, 51, 59, But serology is not a recommended technique especially in 72] where these techniques avoided misdiagnosis [4]. early diagnostic, because Pseudomonas pseudomallei do not Melioidosis may be confirmed or orientated by resistance always cause melioidosis [4]. profile. Indeed, most of Pseudomonas pseudomallei are Medical imaging is widely used. It identifies the infection resistant to colistin (or polymyxin) and to gentamicin but site and helps to find other localizations. Indeed, 57% of pa- sensitive to amoxicillin–clavulanic acid. It is quite un- tients have had multiform melioidosis and 13% have devel- usual and provides some good criteria to distinguish it, oped abscesses on several sites, like in Hadano et al. and notably, from Pseudomonas aeruginosa. Saïdani et al. reports. [22, 89]. 1404 Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408

Table 6 Diagnosis of 77 cases of melioidosis in travelers reported in the Table 6 (continued) literature Patients Deceased Patients Deceased N (% of total) N (% per N (% of total) N (% per category) category) Total 77 5 Total 77 5 Fungal infection 2 (3) – Informative samples* Unknown 51 (66) 2 (5) Blood 38 (49) 5 (13) Misdiagnosis Abscess material 28 (36) 1 (4) Identification of another germ 11 (16) 1 (9) – Cutaneous swab 8 (10) Pneumonia 5 (7) 1 (20) – Sputum 8 (10) Urinary infection or sepsis 5 (6) – – Biopsy 7 (9) Tuberculosis (abscess, pulmonary) 3 (4) – – Cerebral 2 (3) Staphylococcus aureus 2(3) – – Cutaneous 2 (3) Diverticulitis with abscess 1 (1) – – Bone 1 (1) Typhoid fever 1 (1) 1 (100) – Vascular 2 (3) Gastroenteritis 1 (1) – Bronchoalveolar lavage fluid 7 (9) 1 (14) Glioma or abscess 1 (1) – – Urine 4 (6) Unknown 54 (79) 3 (6) Marrow 1 (1) – Cerebrospinal fluid 1 (1) – *Several samples have been informative for some patients Pericardial fluid 1 (1) – **Several methods have been used for some patients Pleural fluid 1 (1) – ***Several pathogens have been sought for some patients Unknown 4 (5) – Method used** The diagnosis of melioidosis is very complex and involves Culture 71 (92) 5 (7) different techniques. As a consequence, many cases would be Molecular biology 37 (48) 3 (8) undiagnosed or identified after a longer period of time. Phenotype 29 (38) 3 (10) Spectrometry 11 (14) 1 (9) Treatment Serology 7 (9) – – Selective media 6 (8) Melioidosis is a therapeutic emergency, because of fatal con- – Chromatography 1 (1) sequences [4]. Empiric antibiotic therapy is most often started – Unknown 2 (3) before germ identification. Antibiotic is usually not relevant or Other pathogens sought*** dose delivery was insufficient, as was observed in our study. Bacteria 22 (29) 3 (14) Even if this treatment may be sufficient for the least serious Mycobacterium tuberculosis 14 (18) – infections, the risk of relapse is increased. Pseudomonas spp. 6 (8) 1 (17) Surgical drainage is required for treating prostatic, muscular Salmonella spp. 3(5) 2(50) and large hepatic abscesses, and septic arthritis [4, 12]. This Legionella 3(4) – choice is questionable for treating disseminated abscesses, Brucella spp. 2 (3) – which most often disappear with antibiotic therapy alone [4]. Staphylococcus aureus 2(3) – After the diagnostic, in most of the cases (56%), treatment Other (chlamydia, Yersinia spp., 2(3) 1(50) regimen and duration followed the current recommendations, Borrelia, Klebsiella spp., including for deceased patients. Doses were not verified because Pasteurella spp., Rickettsia) Virus 11 (14) 1 (9) they were not mentioned in most case reports (Tables 2 and 7). – HIV 8 (10) – Numerous side effects were reported with trimethoprim CMV 2 (3) 1 (50) sulfamethoxazole used for a long time, in up to 40% of pa- EBV 2 (3) 1 (50) tients [4]. In our study, only 14% of them had adverse effects Hepatitis virus 2 (3) 1 (50) with no clear explanation of this discrepancy. But evaluation Other (chikungunya, dengue fever, 2(3) 1(50) and signaling of the side effects are subjective and may differ leptospirosis, retrovirus, parvovirus) across countries. Furthermore, the long-term effects of a 3- Parasites 5 (6) 1 (20) month antimicrobial treatment are quite unpredictable but Malaria 5 (6) 1 (20) have to be taken into account when initiating the therapy Schistosoma 1 (1) – [95, 96]. These consequences are not mentioned in our cases, Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408 1405

Table 7 Treatments of 77 cases of melioidosis in travelers reported in but it may be informative to complete future articles with the literature long-term monitoring data. Patients Deceased There are more resistant strains when doxycycline or N (% of total) N (% per category) amoxicillin–clavulanic acid is used. Many resistant levels Total 77 5 were reported according to the areas. Our rate (17%) is higher than in Malaysia (10%) [97] and in Thailand (13.2%) [98, 99]. Intensive treatment It is nearly seven times higher than those related in Australia Antibiotic choice (2.5%) [100]. These results are consistent with the countries Appropriate 61 (79) 3 (5) where our patients were contaminated. Resistances are re- Inappropriate 5 (7) – sponsible for relapse despite adequate initial treatment [17]. Unknown 4 (5) – Relapse rate (4%) is low but follow-up remains short. One None 7 (9) 2 (29) can assume that the real rate could be higher that this an- Duration nounced; besides, more often than not, relapse can be attrib- Appropriate to guidelines 52 (67) 1 (2) uted to reinfection in endemic areas [101]. Melioidosis thera- Shorter duration 4 (5) – py is long and compliance is essential. At the end of the erad- – Unknown 12 (16) ication treatment, it is hard to follow-up patients despite the None 7 (9) 2 (29) inherent risk of relapse. That is why the warning signs of a Inapplicable 2 (3) 2 (100) relapse and measures to take should be explained to the Maintenance treatment patient. Antibiotic choice Mortality rate (6%) is slightly lower than those reported in Appropriate 63 (82) 1 (2) the literature (10–50%) (Table 8)[17]. This discrepancy is – Inappropriate 3 (4) likely the result of differences in the quality of patient man- Unknown 4 (5) – agement and limited access to care in numerous endemic None 6 (8) 3 (50) countries [4, 88]. A previous study also found a higher mor- Inapplicable 1 (1) 1 (100) tality rate that could be explained by numerous bacteremia, Duration many concomitants diseases, such as diabetes, and a limited Appropriate to guidelines 56 (73) 1 (4) number of cases [17]. Shorter duration 4 (5) – Moreover, no vaccine is available but several are currently Unknown 10 (13) – in development. Significant progress has been made in None 6 (8) 3 (50) subunit-based glycoconjugate vaccines, hence the high expec- Inapplicable 1 (1) 1 (100) tations for potentials candidates in the UK and in the USA in the years to come [102]. At this time, avoiding contact with

Table 8 Main clinical and epidemiological characteristics Our study Saïdani et al. [17] Dan [88]Hadano[89] compared between our study in travelers and review of Geographical area Europe World World Japan melioidosis, which are diagnosed N 77 82 72 14 in non-endemic areas Age (years) 46 50.9 49.6 52.4 Male N (%) 56 (73) 66 (80.5) 55 (76) 14 (100) Age ≤ 18 years N (%) 3 (4) 4 (4.8) 5 (7) – Clinical presentation N (%) Pulmonary 40 (52) 41 (50) 17 (24) 8 (57.1) Cutaneous, soft tissue 27 (35) 23 (28) 9 (12.5) 5 (37.7) Gastrointestinal 13 (8) 14 (17.1) Unknown 3 (21.4) Bacteremia N (%) 33 (43) 42 (51.2) Unknown 9 (62.3) Deceased N (%) 5 (6) 12 (14.6) 12 (17) 2 (14.3) Comorbidities N (%) Diabetes 15 (19) 31 (37.8) 15 (21) 8 (57.1) Chronic hepatic disease, alcoholism 11 (14) 15 (18.3) 5 (7) 2 (14.3) Chronic lung disease, smoking 15 (19) 6 (7.3) 8 (11) – Immunosuppression 6 (8) 4 (4.9) –– None 32 (42) 25 (30.5) Unknown 1 (7.1) 1406 Eur J Clin Microbiol Infect Dis (2019) 38:1395–1408 contaminated water and soil in the endemic area is the best 2. Dance DA, Limmathurotsakul D (2018) Global burden and chal- way of preventing melioidosis [1, 4]. Travelers should drink lenges of melioidosis. Trop Med Infec Dis 3:13 3. Cheng AC, Currie BJ (2005) Melioidosis: epidemiology, patho- only bottled water, eat cooked food, or cleaned with clear physiology, and management. Clin Microbiol Rev 18:383–416 water and wear closed-toe shoes, especially in a rural and 4. Wiersinga WJ, Virk HS, Torres AG et al (2018) Melioidosis. Nat dusty area and during the rainy season. In the case of contact Rev Dis Primer 4:17107 or skin lesion, it is imperative to wash immediately with clear 5. Clark B, Merritt A, Inglis T et al (2018) Clinical features and outcome of patients with cutaneous melioidosis during a nosoco- water and soap. All wounds should be protected and kept mial outbreak in a temperate region of Australia. Intern Med J 48: clean until healing [103]. If high-risk exposure occurs, espe- 461–465 cially patient’s relatives, post-exposure prophylaxis is to as- 6. Dance D (2014) Treatment and prophylaxis of melioidosis. Int J sess on a case-by-case. It consists of oral trimethoprim– Antimicrob Agents 43:310–8.01.005 sulfamethoxazole for 10–21 days. Doxycycline or 7. Valade E, Thibault FM, Biot FV et al (2009) Melioidosis: an – emerging tropical disease. Med Trop Rev Corps Sante Colon 69: amoxicillin clavulanic acid can be administrated as a 437–445 second-line treatment [4, 13]. 8. Agence nationale de sécurité du médicament et des produits de From the imported cases of melioidosis diagnosed in santé Micro-organismes et toxines hautement pathogènes (MOT) Europe between 2000 and 2018, a typical patient would be a https://www.ansm.sante.fr/Dossiers/Micro-organismes-et- toxines-hautement-pathogenes-MOT/Micro-organismes-et- diabetic man over 45 years, with chronic lung disease or active toxines-hautement-pathogenes-MOT/(offset)/0. 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